Abstract
Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimers disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ; however, γ- secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.
Keywords: Protease, amyloid, inhibitors, drug discovery
Current Alzheimer Research
Title: Discovery of Notch-Sparing γ-Secretase Inhibitors
Volume: 7 Issue: 3
Author(s): C.E. Augelli-Szafran, H.-X. Wei, D. Lu, J. Zhang, Y. Gu, T. Yang, P. Osenkowski, W. Ye and M.S. Wolfe
Affiliation:
Keywords: Protease, amyloid, inhibitors, drug discovery
Abstract: Overwhelming evidence supports a central role for the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimers disease (AD), and the proteases that produce Aβ from its precursor protein APP are top targets for therapeutic intervention. Considerable effort has focused on targeting γ-secretase, which generates the C-terminus of Aβ; however, γ- secretase inhibitors cause serious toxicities due to interference with the Notch signaling pathway. We have been working toward compounds that directly alter γ-secretase activity to reduce Aβ production without affecting the proteolysis of Notch. Using purified enzyme and substrate, we have shown that γ-secretase can be selectively inhibited in this way by naphthyl-substituted γ-aminoketones and γ-aminoalcohols. These early hits, however, suffered from chemical instability and/or poor potency. Iterative design, synthesis and evaluation have led to the discovery of Notch-sparing γ-secretase inhibitors with substantially increased potencies in biochemical and cellular assays. These compounds are of low molecular weight and are under evaluation for drug-like properties. The discovery and development of these compounds will be discussed.
Export Options
About this article
Cite this article as:
Augelli-Szafran C.E., Wei H.-X., Lu D., Zhang J., Gu Y., Yang T., Osenkowski P., Ye W. and Wolfe M.S., Discovery of Notch-Sparing γ-Secretase Inhibitors, Current Alzheimer Research 2010; 7 (3) . https://dx.doi.org/10.2174/156720510791050920
DOI https://dx.doi.org/10.2174/156720510791050920 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Onconeural Versus Paraneoplastic Antigens?
Current Medicinal Chemistry Gold Nanomaterials: From Preparation to Pharmaceutical Design and Application
Current Pharmaceutical Design Role of Brassinosteroid in Plant Adaptation to Abiotic Stresses and its Interplay with Other Hormones
Current Protein & Peptide Science Mood-Stabilizers Target the Brain Arachidonic Acid Cascade
Current Molecular Pharmacology Understanding and Improving Treatment Adherence in Patients with Psychotic Disorders: A Review and a Proposed Intervention
Current Psychiatry Reviews The Role of Estradiol and Progesterone in Mucosal HIV-1 Infection, Transmission and Pathogenesis
Current Women`s Health Reviews Alzheimers Disease: An Overview of Current and Emerging Therapeutic Strategies
Current Topics in Medicinal Chemistry Does Phosphodiesterase 11A (PDE11A) Hold Promise as a Future Therapeutic Target?
Current Pharmaceutical Design Soothing the Inflamed Brain: Effect of Non-Steroidal Anti-Inflammatory Drugs on Alzheimers Disease Pathology
CNS & Neurological Disorders - Drug Targets ACE Inhibitor Delapril Prevents Ca<sup>2+</sup>-Dependent Blunting of I<sub>K1</sub> and Ventricular Arrhythmia in Ischemic Heart Disease
Current Molecular Medicine Virulence Factors of Helicobacter pylori: Practical Biomarkers
Recent Patents on Biomarkers The Usefulness of Amyloid Imaging in Predicting the Clinical Outcome After Two Years in Subjects with Mild Cognitive Impairment
Current Alzheimer Research Is There Any Scientific Basis of Hawan to be Used in the Alzheimer’s Disease Prevention/Cure?
Current Traditional Medicine Cerebral Microbleeds Do Not Predict Hemorrhagic Transformation in Acute Ischemic Stroke Patients with Atrial Fibrillation and/or Rheumatic Heart Disease
Current Neurovascular Research Carotid Endarterectomy and Carotid Artery Stenting Lead to Improved Cognitive Performance in Patients with Severe Carotid Artery Stenosis
Current Neurovascular Research Testosterone Replacement Therapy in Older Male Subjective Memory Complainers: Double-Blind Randomized Crossover Placebo-Controlled Clinical Trial of Physiological Assessment and Safety
CNS & Neurological Disorders - Drug Targets Patent Selections :
Recent Patents on Cardiovascular Drug Discovery Quality of Education and Memory Test Performance in Older Men: The New York University Paragraph Recall Test Normative Data
Current Alzheimer Research Triptolide Rescues Spatial Memory Deficits and Amyloid-β Aggregation Accompanied by Inhibition of Inflammatory Responses and MAPKs Activity in APP/PS1 Transgenic Mice
Current Alzheimer Research Is Cdc25 a Druggable Target?
Anti-Cancer Agents in Medicinal Chemistry